Alterations of amine neurotransmitter systems (norepinephrine (NE), serotonin (5HT) and dopamine (DA)) have been indirectly implicated in the pathophysiology of the major mental illnesses, depression and schizophrenia. We have applied new techniques to study the interpretation of neurotransmitter measures from cerebrospinal fluid (CSF), plasma and urine from drug-free patients with affective illness and schizophrenia. New findings include the following: 1. The interrelationships between neurotransmitters as evidenced by correlations of metabolites of NE, 5HT and DA in CSF discriminate between responders and non-responders to antidepressant treatment. Moreover, the same measures appear to discriminate drug free schizophrenics from normal controls. 2. The important question of whether variations in at least one type of neurotransmitter receptor on cells obtainable from blood can be explained primarily on the basis of circulating agonist has been answered. Lymphocyte beta receptor parameters have been clearly shown to vary independently of plasma norepinephrine and epinephrine. 3. Longitudinal studies of patients with affective illness have included repeat biochemical measures in drug-free states during which mood was normal. Surprisingly, the exaggerated plasma NE response to going from a supine to standing position which is consistently noted in the depressed state persisted during the "well" state. Thus, investigation of the NE system may reveal a trait abnormality in persons susceptible to affective disorder and provide a means of identifying persons at risk.